Download Irbesartan/Hydrochlorothiazide

Product Information
Avapro HCT (Irbesartan/Hydrochlorothiazide]
NAME OF THE MEDICINE
Australian Approved Name
Irbesartan/Hydrochlorothiazide
Irbesartan: 2-butyl-3-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-1,3-diazaspiro [4,4] non-1-en4-one.
Hydrochlorothiazide:
dioxide.
6-chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-sulfonamide
Chemical Structure
The chemical structure of irbesartan
1,1-
is:
O
N
N
(CH 2)3CH3
C25H28N6O
N
N
N
N
MW = 428.5
H
Irbesartan
CAS number: 138402-11-6
The chemical structure of hydrochlorothiazide is:
O
H2N
S
Cl
O
O
S
O
N
H
N
C7H8ClN3O4S2
H
MW = 297.7
Hydrochlorothiazide
CAS number: CAS-58-93-5
DESCRIPTION
Avapro HCT (irbesartan/hydrochlorothiazide) is an oral antihypertensive agent combining a
nonpeptide angiotensin II receptor (AT1 subtype) antagonist, irbesartan, and a thiazide diuretic,
hydrochlorothiazide.
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Irbesartan is a white to off-white crystalline powder. It is a relatively non-polar compound with a
partition coefficient (octanol-water) of 10.1 at a pH of 7.4. Irbesartan is slightly soluble in
alcohol and methylene chloride, and practically insoluble in water.
Hydrochlorothiazide is a white crystalline powder. It is slightly soluble in water but freely
soluble in sodium hydroxide solution.
Avapro HCT 150/12.5 tablets contain 150mg of irbesartan and 12.5mg of hydrochlorothiazide
and are peach to mottled peach coloured, biconvex, oval-shaped, film-coated tablets debossed
with a heart on one side and the number “2875” on the other side.
Avapro HCT 300/12.5 tablets contain 300mg of irbesartan and 12.5mg of hydrochlorothiazide
and are peach to mottled peach coloured, biconvex, oval-shaped, film-coated tablets debossed
with a heart on one side and the number “2876” on the other side.
Avapro HCT 300/25 tablets contain 300mg of irbesartan and 25mg of hydrochlorothiazide and
are pink, biconvex, oval-shaped, film-coated tablets debossed with a heart on one side and the
number “2788” on the other side.
The inactive ingredients in Avapro HCT 150/12.5 & 300/12.5 tablets include: carnauba wax,
croscarmellose sodium, hypromellose, iron oxide red CI 77491, iron oxide yellow CI 77492,
lactose, macrogol 3000, magnesium stearate, microcrystalline cellulose, silicon dioxide, and
titanium dioxide.
The inactive ingredients in Avapro HCT 300/25 tablets include: carnauba wax, croscarmellose
sodium, hypromellose, iron oxide black CI 77499, iron oxide red CI 77491, iron oxide yellow CI
77492, lactose, macrogol 3350, magnesium stearate, microcrystalline cellulose, pregelatinised
maize starch, silicon dioxide, and titanium dioxide.
PHARMACOLOGY
Pharmacodynamics
Irbesartan is a specific antagonist of angiotensin II receptors (AT1 subtype). Angiotensin II is an
important component of the renin-angiotensin system and is involved in the pathophysiology of
hypertension and in sodium homeostasis. Irbesartan does not require metabolic activation for its
activity.
Irbesartan blocks the potent vasoconstrictor and aldosterone-secreting effects of angiotensin II by
selective antagonism of the angiotensin II (AT1 subtype) receptors localized on vascular smooth
muscle cells and in the adrenal cortex. It has no agonist activity at the AT1 receptor and a much
greater affinity (more than 8500-fold) for the AT1 receptor than for the AT2 receptor (a receptor
that has not been shown to be associated with cardiovascular homeostasis).
Irbesartan does not inhibit enzymes involved in the renin-angiotensin system (i.e., renin,
angiotensin converting enzyme [ACE]) or affect other hormone receptors or ion channels
involved in the cardiovascular regulation of blood pressure and sodium homeostasis.
Hydrochlorothiazide is a benzothiadiazine (thiazide) diuretic with diuretic, natriuretic and
antihypertensive effects. The mechanism of antihypertensive effect of thiazide diuretics, such as
hydrochlorothiazide is not fully known. Thiazides affect the renal tubular mechanism of
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electrolyte reabsorption, increasing excretion of sodium and chloride in approximately equivalent
amounts. Natriuresis causes a secondary loss of potassium and bicarbonate. Hydrochlorothiazide
increases plasma renin activity, increases aldosterone secretion, and decreases serum potassium.
Coadministration of an angiotensin II receptor antagonist tends to reverse the potassium loss
associated with thiazide diuretics.
Pharmacokinetics
Concomitant administration of hydrochlorothiazide and irbesartan has no effect on the
pharmacokinetics of either drug.
Absorption
The oral bioavailabilities of irbesartan and hydrochlorothiazide measured after administration of
Avapro HCT are similar to the bioavailabilities of irbesartan and hydrochlorothiazide
administered as separate entities. The absolute oral bioavailability for irbesartan has previously
been shown to be 60-80% whilst the absolute oral bioavailability for hydrochlorothiazide is
documented as 50-80%.
Food does not affect the bioavailability of Avapro HCT. Peak plasma concentrations occur 1.5-2
hours after oral administration for irbesartan and 1-2.5 hours for hydrochlorothiazide.
Distribution
Irbesartan is 90% protein-bound in the plasma, and has negligible binding to cellular components
of blood. The volume of distribution is 53-93 litres (0.72-1.24 Litres/Kg). Hydrochlorothiazide
is 68% protein-bound in the plasma, and its apparent volume of distribution is 0.83 -1.141
Litres/Kg.
Metabolism
In plasma, unchanged irbesartan accounts for more than 80% of the circulating radioactivity
following oral or intravenous administration of 14C irbesartan. Irbesartan is metabolized by the
liver via glucuronide conjugation and oxidation. The major circulating metabolite is irbesartan
glucuronide (~6%). Irbesartan undergoes oxidation primarily by the cytochrome P450 isoenzyme
CYP2C9; isoenzyme CYP3A4 has negligible effect. It is not metabolized by, nor does it
substantially induce or inhibit most isoenzymes commonly associated with drug metabolism (i.e.,
CYP1A1, CYP1A2, CYP2A6, CYP2B6, CYP2D6, or CYP2E1). Irbesartan does not induce nor
inhibit isoenzyme CYP3A4.
Hydrochlorothiazide is not metabolized.
Elimination
Irbesartan and its metabolites are excreted by both biliary and renal routes. About 20% of the
administered radioactivity after an oral or intravenous dose of 14C irbesartan is recovered in urine
with the remainder in the faeces. Less than 2% of the dose is excreted in urine as unchanged
irbesartan.
The terminal elimination half-life (t½) of irbesartan from plasma is 11-15 hours. The total body
clearance of intravenously administered irbesartan is 157-176 mL/min, of which 3.0-3.5mL/min
is renal clearance. Irbesartan exhibits linear pharmacokinetics over the therapeutic dose range.
Steady-state plasma concentrations are attained within 3 days after initiation of a once-daily
dosing regimen. Limited accumulation (<20%) is observed in plasma upon repeated once-daily
dosing.
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Hydrochlorothiazide is eliminated by the kidneys. The mean plasma half-life (t½) of
hydrochlorothiazide from plasma reportedly ranges from 5-15 hours.
Special Populations
In male and female hypertensive subjects, higher (11-44%) plasma concentrations of irbesartan
were observed in females than in males, although, following multiple dosing, males and females
did not show differences in either accumulation or elimination half-life. No gender-specific
differences in clinical effect have been observed.
In elderly (male and female) normotensive subjects (65-80 years) with clinically normal renal and
hepatic function, the plasma AUC and peak plasma concentration (Cmax) of irbesartan are
approximately 20%-50% greater than those observed in younger subjects (18-40 years).
Regardless of age, the elimination half-life is comparable. No significant age-related differences
in clinical effect have been observed. The area under the plasma concentration time curve (AUC)
for hydrochlorothiazide was elevated in the elderly group following multiple dosing consistent
with previously published data.
In black and white normotensive subjects, the plasma AUC and t½ of irbesartan are
approximately 20-25% greater in blacks than in whites; the peak plasma concentrations (Cmax) of
irbesartan are essentially equivalent.
In patients with renal impairment (regardless of degree) and in haemodialysis patients, the
pharmacokinetics of irbesartan are not significantly altered. Irbesartan is not removed by
haemodialysis. In patients with severe renal impairment (creatinine clearance <20 mL/min), the
elimination half-life of hydrochlorothiazide was reported to increase to 21 hours.
In patients with hepatic insufficiency due to mild to moderate cirrhosis, the pharmacokinetics of
irbesartan are not significantly altered.
CLINICAL TRIALS
Based on data from placebo-controlled clinical trials, the following effects were noted. The
blood pressure lowering effect of irbesartan in combination with hydrochlorothiazide was
apparent after the first dose and substantially present within 1-2 weeks, with the maximal effect
occurring by 6-8 weeks. In long-term follow-up studies, the blood pressure lowering effect of
irbesartan/hydrochlorothiazide with dose-to-response addition of adjunctive therapy was
maintained for over one year.
The combination of hydrochlorothiazide and irbesartan produced dose-related additive reductions
in blood pressure across their therapeutic dose ranges.
The addition of 12.5mg
hydrochlorothiazide to 300 mg irbesartan once daily in patients not adequately controlled on 300
mg irbesartan alone resulted in further placebo-corrected diastolic blood pressure reductions at
trough (24 hours post dosing) of 6.1 mmHg. The combination of 300 mg irbesartan and 12.5 mg
hydrochlorothiazide resulted in an overall placebo-subtracted systolic/diastolic reductions of up to
13.6/11.5 mmHg.
Limited clinical data (7 out of 22 patients) suggest that patients not controlled with the 300/12.5
mg combination may respond when uptitrated to 300/25 mg. In these patients, an incremental
blood pressure lowering effect was observed for both SBP and DBP (13.3 and 8.3 mm Hg,
respectively).
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Once daily dosing with 150 mg irbesartan and 12.5 mg hydrochlorothiazide showed
systolic/diastolic mean placebo-adjusted blood pressure reductions at trough (24 hours postdosing) of 12.9/6.9mmHg. Peak effects occurred at 3-6 hours.
When assessed by ambulatory blood pressure monitoring, Avapro HCT 150/12.5 once daily
produced consistent reduction in blood pressure over the 24 hours period with a mean 24-hour
placebo-subtracted systolic/diastolic reductions of 15.8/10.0 mmHg. The observed trough-topeak effects were at least 68% of the corresponding placebo-subtracted peak diastolic and peak
systolic responses.
In a clinical trial with patients not adequately controlled on 25 mg hydrochlorothiazide alone after
4 weeks’ treatment , the addition of irbesartan (with dose-to-response uptitration from 75mg to
150mg at 6 weeks) produced mean systolic/diastolic reductions at 12 weeks which were 11.1/7.2
mm Hg greater than hydrochlorothiazide alone.
Blood pressure was lowered to about the same extent in both standing and supine positions.
Orthostatic effects were infrequent, but may be expected to occur in patients who develop
intercurrent sodium and/or volume-depletion.
The effect of the combination of irbesartan and hydrochlorothiazide on morbidity and mortality
has not been studied. Epidemiological studies have shown that long term treatment with
hydrochlorothiazide reduces the risk of cardiovascular mortality and morbidity.
The effectiveness of irbesartan/hydrochlorothiazide was not influenced by age, race, or gender.
The overall antihypertensive response to the combination was similar for black and non black
patients.
After withdrawal of irbesartan, blood pressure gradually returned toward baseline. Rebound
hypertension was not observed with irbesartan or hydrochlorothiazide.
With hydrochlorothiazide, onset of diuresis occurred in 2 hours, and peak effect occurred at about
4 hours, while the action persisted for approximately 6-12 hours.
INDICATIONS
Avapro HCT is indicated for the treatment of hypertension. Treatment should not be initiated
with this fixed-dose combination.
CONTRAINDICATIONS
Avapro HCT is contraindicated in patients who are hypersensitive to irbesartan, sulfonamidederived drugs (e.g., thiazides), or to any other component of the Avapro HCT formulation. In
general, hypersensitivity reactions are more likely to occur in patients with a history of allergy or
bronchial asthma.
Avapro HCT is contraindicated in patients who are anuric.
Do not co-administer Avapro HCT with aliskiren-containing medicines in patients with diabetes
or with moderate to severe renal impairment.
Do not co-administer Avapro HCT with ACE inhibitors in patients with diabetic nephropathy.
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Pregnancy. (See PRECAUTIONS – use in Pregnancy)
PRECAUTIONS
Hypotension - Volume - Depleted Patients
Avapro HCT has been rarely associated with hypotension in hypertensive patients without other
risk factors for hypotension. Symptomatic hypotension may be expected to occur in patients who
have been sodium and/or volume depleted by vigorous diuretic therapy and/or dietary salt
restriction, or vomiting and/or diarrhoea or haemodialysis. Volume and/or sodium-depletion
should be corrected before initiating therapy with Avapro HCT. Thiazides may potentiate the
action of other antihypertensive drugs (see INTERACTIONS OTHER MEDICINES).
Renal Impairment
As a consequence of inhibiting the renin-angiotensin-aldosterone system, changes in renal
function during therapy with Avapro HCT may be anticipated in susceptible individuals. In
patients whose renal function depends on the activity of the renin-angiotensin-aldosterone system
(e.g., hypertensive patients with renal artery stenosis in one or both kidneys, or patients with
severe congestive heart failure), treatment with drugs that affect this system has been associated
with oliguria and/or progressive azotemia and (rarely) with acute renal failure and/or death. The
possibility of a similar effect occurring with the use of an angiotensin II receptor antagonist,
including Avapro HCT cannot be excluded.
There is no experience with Avapro HCT in patients with a recent renal transplant.
Avapro HCT is not recommended for patients with severe renal disease (creatinine clearance ≤ 30
mL/min) (see CONTRAINDICATIONS - anuric patients). Hydrochlorothiazide-associated
precipitation of azotemia may occur in patients with impaired renal function. As experience is
limited in patients with a creatinine clearance >30 and < 60mL/min, Avapro HCT should be
administered with caution to such patients.
Dual blockade of the Renin-Angiotensin-Aldosterone System (RAAS)
Dual blockade of the RAAS by combining Avapro HCT with an ACE inhibitor or with aliskiren
is not recommended since there are increased risk of hypotension, hyperkalemia, and changes in
renal function. The use of Avapro HCT in combination with aliskiren is contraindicated in patient
with diabetes mellitus or renal impairment (see CONTRAINDICATIONS).
The use of Avapro HCT in combination with aliskiren is contraindicated in patients with diabetes
mellitus or with moderate to severe renal impairment.
The use of Avapro HCT in combination with an ACE inhibitor is contraindicated in patients with
diabetic nephropathy (See ‘CONTRAINDICATIONS’ and ‘INTERACTIONS’).
Renal Artery Stenosis
See comments under Renal Impairment above.
Primary Aldosteronism
Patients with primary aldosteronism generally will not respond to antihypertensive medicines
acting through inhibition of the renin-angiotensin system. Therefore the use of Avapro HCT is
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not recommended.
Postsympathectomy
The antihypertensive effects of thiazide diuretics may be increased in the postsympathectomy
patient.
Impaired Hepatic Function
Avapro HCT should be used with caution in patients with impaired hepatic function or
progressive liver disease, since minor alterations in fluid and electrolyte balance may precipitate
hepatic coma.
Fluid and Electrolyte Imbalance
Thiazides, including HCTZ, can cause fluid or electrolyte imbalance (hypokalemia, hyponatremia
and hypochloremic alkalosis). Although hypokalemia may develop when thiazide diuretics are
used alone, especially with higher doses, concurrent therapy with irbesartan reduces the frequency
of diuretic-induced hypokalemia. Chloride deficit is generally mild and usually does not require
treatment. Calcium excretion is decreased by thiazides which may cause intermittent and slight
elevation of serum calcium.
Marked hypercalcemia suggests the possibility of
hyperparathyroidism. Thiazides should be discontinued before carrying out tests for parathyroid
function. Thiazides have been shown to increase the urinary excretion of magnesium, which may
result in hypomagnesaemia.
Monitoring of laboratory parameters may be necessary in patients at risk of electrolyte imbalance.
Metabolic and Endocrine Effects
Hyperuricemia may occur, and an acute attack of gout may be precipitated in certain patients
receiving thiazide therapy. Insulin requirements in diabetic patients may be increased and latent
diabetes mellitus may become manifest during thiazide administration. Increases in cholesterol
and triglyceride levels have been associated with thiazide diuretic therapy, however, minimal or
no effects were reported at the 12.5 mg hydrochlorothiazide dose contained in Avapro HCT.
Monitoring of laboratory parameters may be necessary in patients at risk of metabolic
disturbances.
Systemic Lupus Erythematosus
Exacerbation or activation of systemic lupus erythematosus has been reported with the use of
thiazide diuretics.
Acute Myopia and Secondary Acute Angle-Closure Glaucoma
Sulfonamide, or sulfonamide derivative, drugs can cause an idiosyncratic reaction, resulting in
transient myopia and acute angle-closure glaucoma. While hydrochlorothiazide is a sulfonamide,
isolated cases of acute angle-closure glaucoma without definite causal association have been
reported so far with hydrochlorothiazide. Symptoms include acute onset of decreased visual
acuity or ocular pain and typically occur within hours to weeks of drug initiation. Untreated acute
angle-closure glaucoma can lead to permanent vision loss. The primary treatment is to discontinue
drug intake as rapidly as possible. Prompt medical or surgical treatments may need to be
considered if the intraocular pressure remains uncontrolled. Risk factors for developing acute
angle-closure glaucoma may include a history of sulfonamide or penicillin allergy.
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Heart Failure
The safety of irbesartan in the presence of heart failure has not been fully defined. Sudden death
has occurred in some studies of patients with heart failure, and although such deaths may have
reflected the natural history of the underlying heart failure, caution is recommended when treating
such patients with irbesartan.
Cardiac Arrhythmia
At this time, experience is limited with irbesartan in the treatment of patients with ventricular
dysfunction or cardiac arrhythmias; caution is advised.
Effects on Fertility
The effects of hydrochlorothiazide and the irbesartan/hydrochlorothiazide combination on fertility
have not been evaluated in animal studies. However, with irbesartan alone, fertility and
reproductive performance were not affected in studies of male and female rats at oral doses up to
650mg/kg/day (approximately 3 [male] and 8[female] fold higher exposure based on AUC, than
that of humans at the maximum recommended clinical dose of 300mg/day.)
Use in Pregnancy Category D
Drugs that act directly on the renin-angiotensin system can cause foetal and neonatal
morbidity and death when administered to pregnant women. Several dozen cases have been
reported in the world literature in patients who were taking angiotensin-converting enzyme
inhibitors. When pregnancy is detected, Avapro HCT should be discontinued as soon as
possible.
The use of drugs that act directly on the renin-angiotensin system during the second and third
trimesters of pregnancy have been associated with foetal and neonatal injury, including
hypotension, neonatal skull hypoplasia, anuria, reversible or irreversible renal failure, and
death. Oligohydramnios has also been reported, presumably resulting from decreased foetal
renal function; oligohydramnios in this setting has been associated with foetal limb
contractures, craniofacial deformation and hypoplastic lung development. Prematurity,
intrauterine growth retardation and patent ductus arteriosus have also been reported, although
it is not clear whether these occurrences were due to exposure to the drug.
These adverse effects do not appear to have resulted from intrauterine drug exposure that has
been limited to the first trimester. Mothers whose embryos and foetuses are exposed to an
angiotensin II receptor antagonist only during the first trimester should be so informed.
Nonetheless, when patients become pregnant, physicians should have the patient discontinue
the use of Avapro HCT as soon as possible.
Infants with histories of in utero exposure to an angiotensin II receptor antagonist should be
closely observed for hypotension, oliguria and hyperkalemia.
Thiazides cross the placental barrier and appear in cord blood. The routine use of diuretics in
otherwise healthy pregnant women is not recommended and exposes mother and foetus to
unnecessary hazard, including foetal or neonatal jaundice, thrombocytopenia and possibly other
adverse reactions which have occurred in the adult.
No teratogenic effects were seen in rats given irbesartan and hydrochlorothiazide in combination
at doses as high as 150/150mg/kg/day. When pregnant rats were treated with irbesartan alone
from day 0 to day 20 of gestation, at doses of 50 mg/kg/day and higher, transient effects
(increased renal pelvic cavitation, hydroureter or subcutaneous oedema) were noted in full term
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rat foetuses but not in young animals necropsied after six weeks of age. In pregnant rabbits, at
doses of 30mg/kg/day, maternal mortality, abortion and early foetal resorptions were noted. No
teratogenic effects were observed in the rat or the rabbit.
Use in Lactation
Irbesartan is excreted in the milk of lactating rats. It is not known whether irbesartan or its
metabolites are excreted in human milk. Hydrochlorothiazide is excreted in human breast milk.
Thiazides in high doses causing intense diuresis can inhibit the milk production. The use of
Avapro HCT during breastfeeding is not recommended.
Because of the potential risk to the infant, a decision should be made whether to discontinue
breast feeding or to discontinue the drug, taking into account the importance of Avapro HCT to
the therapy of the mother.
Paediatric Use
Safety and effectiveness in paediatric patients have not been established.
Use in the Elderly
Among patients who received Avapro HCT in clinical studies, no overall differences in efficacy
or safety were observed between older patients (65 years or older) and younger patients.
Genotoxicity
Irbesartan and the irbesartan/hydrochlorothiazide combination were not genotoxic in a series of
assays for gene-mutagenic activity in bacterial and mammalian cells, and for clastogenic effects
in vitro and in vivo. Hydrochlorothiazide alone was not genotoxic in a gene-mutation assay in
bacterial cells, or in tests for clastogenic activity in vitro and in vivo. However, positive results
were obtained in a mammalian cell assay for gene mutation (mouse lymphoma cell assay), and in
two other tests (sister chromatid exchange assay in Chinese hamster ovary cells and nondisjunction assay in Aspergillus nidulans).
Carcinogenicity
The carcinogenic potential of irbesartan and hydrochlorothiazide in combination has not been
evaluated in animal studies. However, the carcinogenic potential of irbesartan was assessed in
two 104 week studies in mice and rats. No carcinogenic potential was observed in either species
at doses of up to 500mg/kg/day (male rats) and 1000mg/kg/day (mice and female rats). The AUC
based exposure levels were 3 - 6 fold higher in mice, 3 fold higher in male rats and 25 fold higher
in female rats than that of humans at the maximum recommended clinical dose of 300mg/day.
With hydrochlorothiazide two-year feeding studies in mice and rats uncovered no evidence of
carcinogenic potential in female mice at doses up to approximately 600mg/kg/day, or in male and
female rats at doses up to approximately 100mg/kg/day. The studies, however, uncovered
equivocal evidence for hepatocarcinogenicity in male mice treated with hydrochlorothiazide at
approximately 600mg/kg/day.
Effect on Laboratory Tests:
In premarketing controlled clinical trials, clinically important changes in standard laboratory
parameters were rarely associated with administration of Avapro HCT tablets.
Creatinine, Blood Urea Nitrogen: Minor increases in blood urea nitrogen (BUN) or serum
creatinine were observed in 2.3 and 1.1 percent respectively, of patients with essential
hypertension treated with Avapro HCT alone. No patient discontinued taking Avapro HCT
due to increased BUN. One patient discontinued taking Avapro HCT
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due to a minor increase in creatinine.
Haemoglobin: mean decreases of approximately 0.2g/dL occurred in patients treated with
Avapro HCT alone, but were rarely of clinical importance. This compared to a mean of
0.4g/dL in patients receiving placebo. No patients were discontinued due to anaemia.
Liver Function Tests: Occasional elevations of liver enzymes and/or serum bilirubin have
occurred. In patients with essential hypertension treated with Avapro HCT alone, one patient
was discontinued due to elevated liver enzymes.
Serum Electrolytes: In double-blind clinical trials of various doses of irbesartan and
hydrochlorothiazide, the incidence of hypertensive patients who developed hypokalemia (serum
potassium <3.5 mmol/L) was 7.5% versus 6.0% for placebo; the incidence of hyperkalemia
(serum potassium >5.7mmol/L) was < 1.0% versus 1.7% for placebo. No patient discontinued due
to increases or decreases in serum potassium. Overall, the combination of irbesartan and
hydrochlorothiazide had no effect on serum potassium. Higher doses of irbesartan ameliorated the
hypokalemic response to hydrochlorothiazide. (See PRECAUTIONS- Fluid and Electrolyte
Imbalance).
INTERACTIONS WITH OTHER MEDICINES
Based on in vitro data, no interactions with irbesartan would be expected to occur with drugs
whose metabolism is dependent upon cytochrome P450 isoenzymes CYP1A1, CYP1A2,
CYP2A6, CYP2B6, CYP2D6, CYP2E1 or CYP3A4. Irbesartan is primarily metabolized by
CYP2C9, however, during clinical interaction studies, no significant pharmacokinetic and
pharmacodynamic interactions were observed when irbesartan was co-administered with warfarin
(a drug metabolized by CYP2C9).
Irbesartan does not affect the pharmacokinetics of digoxin or simvastatin. The pharmacokinetics
of irbesartan are not affected by coadministration with nifedipine or hydrochlorothiazide.
Based on experience with the use of other drugs that affect the renin-angiotensin system,
concomitant use of potassium-sparing diuretics, potassium supplements, salt substitutes
containing potassium or other medicinal products that may increase kalaemia with irbesartan may
lead to increases in serum potassium, sometimes severe, and requires close monitoring of serum
potassium. Concurrent therapy with hydrochlorothiazide may reduce the frequency of this effect.
Alcohol, barbiturates or narcotics - Potentiation of thiazide diuretic - induced orthostatic
hypotension may occur.
Antidiabetic drugs (oral agents and insulin) - Thiazides may elevate blood glucose levels thus,
dosage adjustments of antidiabetic agents may be necessary.
Antigout medication - Dosage adjustments of antigout medication may be needed since HCTZ
may raise the blood level of uric acid.
Cardiac glycosides (e.g., digoxin) and other antiarrhythmic drugs (e.g., sotalol) - Diureticinduced hypokalemia may accentuate cardiac arrhythmias.
Calcium salts - Thiazide diuretics may increase serum calcium levels due to decreased excretion.
If calcium or a calcium sparing drug (e.g. Vitamin D therapy) is prescribed, serum calcium levels
avapro-hct-ccdsv12-piv8-26jun15
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should be monitored and calcium dosage adjusted accordingly.
Cholestyramine resin and colestipol HCl - May delay or decrease absorption of HCTZ. Avapro
HCT should be taken at least one hour before or four hours after these medications.
Lithium - Diuretic agents reduce the renal clearance of lithium and increase the risk of lithium
toxicity. Increases in serum lithium concentrations and lithium toxicity have been reported with
concomitant use of irbesartan. Monitor lithium levels in patients receiving irbesartan and lithium.
Inhibitors of Endogenous Prostaglandin Synthesis (i.e., NSAIDs) - In some patients, these
agents can reduce the effects of thiazide diuretics.
Other diuretics and antihypertensive medications - The thiazide component of Avapro HCT
may potentiate the actions of other antihypertensive drugs, especially ganglionic or peripheral
adrenergic-blocking drugs. HCTZ may interact with diazoxide; blood glucose, serum uric acid
levels and blood pressure should be monitored.
Combination use of ACE inhibitors or angiotensin receptor antagonists, anti-inflammatory
drugs and thiazide diuretics - Concomitant use of a renin-angiotensin system inhibiting drug
(ACE-inhibitor or angiotensin receptor antagonist), and an anti-inflammatory drug (NSAID,
including COX-2 inhibitor) alone or with a thiazide diuretic may increase the risk of renal
impairment, including possible acute renal failure. These effects are usually reversible. This
includes use in fixed-combination products containing more than one class of drug. The
combination of these agents should be administered with caution, especially in the elderly,
volume-depleted, and in patients with pre-existing renal impairment. Renal function (serum
creatinine) should be monitored after initiation of concomitant therapy, and periodically
thereafter. The antihypertensive effect of angiotensin II receptor antagonists, including
irbesartan, may be attenuated by NSAIDs including selective COX-2 inhibitors.
The use of Avapro HCT in combination with an ACE inhibitor is contraindicated in patients with
diabetic nephropathy (See ‘CONTRAINDICATIONS’ and ‘INTERACTIONS’).
Renin inhibitor
The combination of Avapro HCT with aliskiren-containing medicinal products is
contraindicated in patients with diabetes mellitus or moderate to severe renal impairment and
is not recommended in other patients (see CONTRAINDICATIONS).
Angiotensin-Converting Enzyme inhibitors (ACE inhibitors)
The use of Avapro HCT in combination with an ACE inhibitor is contraindicated in patients with
diabetic nephropathy and is not recommended in other patients.
Drugs used during surgery - The effects of nondepolarizing muscle relaxants (e.g.,
tubocurarine), preanaesthetics and anaesthetics used in surgery may be potentiated by HCTZ;
dosage adjustments may be required. Preanesthetic and anaesthetic agents should be given in
reduced dosage, and if possible, HCTZ therapy discontinued one week prior to surgery.
Carbamazepine - concomitant use of carbamazepine and hydrochlorothiazide has been associated
with the risk of symptomatic hyponatraemia. Electrolytes should be monitored during
concomitant use. If possible, another class of diuretics should be used.
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Pressor amines (eg noradrenaline) - Due to the thiazide component there is a possible decreased
response to pressor amines but not sufficient to preclude their use.
Corticosteroids, ACTH - Intensified electrolyte depletion , particularly hypokalemia can occur
with thiazide use.
Other interactions - The hypoglycaemic effect of beta-blockers and diazoxide may be enhanced
by thiazides. Anticholinergic agents (eg atropine) may increase the bioavailability of thiazidetype diuretics by decreasing gastrointestinal motility and stomach emptying rate. Thiazides may
increase the risk of adverse effects caused by amantadine. Thiazides may reduce the renal
excretion of cytotoxic drugs (eg cyclophosphamide, methotrexate) and potentiate their
myelosuppressive effects.
Driving/Operating Machinery
The effects of Avapro HCT on the ability to drive motor vehicles or operate machinery have not
been specifically studied, but based on its pharmacodynamic properties. Avapro HCT is unlikely
to affect this ability. When driving vehicles or operating machinery, it should be taken into
account that occasionally dizziness may occur during treatment of hypertension.
ADVERSE EFFECTS
The combination of irbesartan and hydrochlorothiazide has been evaluated for safety in
approximately 2750 subjects in clinical studies, including 1540 hypertensive patients treated for
over 6 months and over 960 patients treated for one year or more. Adverse events in patients
receiving Avapro HCT were generally mild and transient with no relationship to dose. The
incidence of adverse events was not related to age, gender, or race.
In placebo-controlled clinical studies, including 898 irbesartan/HCTZ-treated patients (usual
duration of treatment 2 to 3 months), discontinuations due to any clinical or laboratory adverse
event were 3.6 percent for irbesartan/HCTZ-treated patients and 6.8 percent for placebo-treated
patients (p=0.023).
Adverse events occurring in at least 1% of patients treated with irbesartan/HCTZ, in placebo
controlled trials are shown in the table below.
The incidences of the same adverse events in the placebo, irbesartan and hydrochlorothiazide
control groups are also shown.
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Adverse Events in Placebo-Controlled Hypertension Trials
Incidence
Percentage (%) of Patients
BODY SYSTEM/EVENT
Irbesartan/HCTZ
n=898
Irbesartan
n=400
HCTZ
n=380
Placebo
n=236
General
Chest pain
Fatigue
Influenza
1.8
6.5 *
2.8
1.5
4.0
2.0
1.6
3.2
1.8
1.3
3.0
1.3
Cardiovascular
Oedema
Tachycardia
3.1
1.2
1.5
0.5
1.6
0.5
2.5
0.4
Dermatology
Rash
1.2
1.8
3.2
1.7
Gastrointestinal
Abdominal pain
Anorectal disorder
Diarrhoea
Dyspepsia/heartburn
Nausea/vomiting
1.7
1.0
2.1
2.1
3.2 *
1.5
0.3
2.8
0.3
1.5
1.6
0
1.1
1.6
2.4
0.8
0.4
3.4
0.8
0.4
Immunology/Sensitivity disorder
Allergy
1.1
0.5
0.5
0
Musculoskeletal/Connective Tissue
Musc/skeletal pain
Muscle cramp
Musculoskeletal trauma
6.5
1.0
1.3
6.0
0.8
2.0
9.7 *
2.1
1.8
4.7
1.3
0.8
Nervous System
Anxiety/nervousness
Dizziness
Dizziness orthostatic
Headache
1.0
7.6
1.1
11.0 *
1.0
5.5
1.0
9.3 *
0.5
4.7
0.8
11.6
1.7
4.2
0.4
16.1
Renal/Genitourinary
Abnormal urination
UTI
1.9
1.6
0.5
1.5
2.1
2.4
0.8
2.5
Respiratory
Cough
Pharyngitis
Rhinitis
Sinus abnormality
Upper respiratory infection
2.2
2.1
1.9
2.9
5.6
2.3
2.3
2.0
4.5
8.3
2.6
2.9
1.6
3.2
7.1
3.0
1.7
2.5
4.7
5.5
* Statistically significant difference compared with placebo, p<0.05
Adverse reactions (clinical events probably or possibly related to therapy as determined by the
clinical investigator) that occurred in more than 2 hypertensive patients when they were taking
irbesartan/ HCTZ and no additional study medications in premarketing clinical trials involving
2700 subjects, and that were not reported in the above tabulation of adverse events, are listed in
the following section.
These adverse reactions have been classified using standard terminology and are categorized by
avapro-hct-ccdsv12-piv8-26jun15
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body system. They are listed in order of decreasing frequency according to the following
definitions:
common: those adverse reactions occurring on one or more occasions in at least 1/100 but less
than 1/10 patients;
uncommon: adverse reactions occurring in at least 1/1000 but less than 1/100 patients;
rare: those adverse reactions occurring in less than 1/1000 patients.
Cardiovascular: Uncommon - bradycardia; disturbance of cardiac rhythm; subjective disturbance
of cardiac rhythm; disturbance of ventricular rhythm; ECG abnormality; flushing; hypotension;
orthostatic hypotension; syncope.
Dermatologic: Uncommon - pruritus; skin discomfort
Endocrine/Metabolic: Common - sexual dysfunction; Uncommon - diabetes; gout; hot flashes;
libido changes.
Gastrointestinal: Uncommon - constipation; decreased appetite; abdominal distention; dry
mouth; epigastric pain; flatulence; gastroesophageal reflux.
General: Uncommon - cold sensation; hyperhidrosis; malaise; weakness; weight gain.
Musculoskeletal/Connective Tissue: Uncommon - abnormal reflexes; muscle ache; myalgia;
extremity swelling; extremity weakness.
Nervous System: Uncommon - coordination disturbance; depression; emotional
lability/disturbance; numbness; paresthesia; sleep disturbance; somnolence; vertigo.
Respiratory: Uncommon - dry nasopharynx; dyspnea; wheezing.
Special Senses: Uncommon - abnormal hearing; taste disturbance; vision disturbance.
Other clinical adverse reactions reported with the use of irbesartan or hydrochlorothiazide alone
include:
Cardiovascular: subjective rhythm disturbance, flushing, ECG abnormality, cardiac murmur,
cardiac rhythm disturbance, orthostatic hypotension, atrial rhythm disturbance, conduction
disorder, myocardial infarction.
Dermatologic: facial erythema, dermatitis, acne, scalp-hair abnormality.
Endocrine/Metabolic/ Electrolyte Imbalance: breast disorder, hyperglycaemia, glycosuria,
hyperuricaemia, electrolyte imbalance (including hyponatraemia and hypokalaemia),
Gastrointestinal: abnormal stool, increased appetite, oral lesion, dysphagia, oesophagitis,
anorexia, gastric irritation, jaundice (intrahepatic cholestatic jaundice), pancreatitis, sialadenitis,
xanthopsia.
General: weakness, weight gain, warmth sensation, pain.
Haematopoietic: leucopenia, neutropenia/agranulocytosis, thrombocytopenia, anaemia, aplastic
anaemia, haemolytic anaemia.
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Immunology/ Sensitivity Disorder: upper extremity oedema, head/neck oedema,
photosensitivity reactions, fever, urticaria, necrotizing angiitis, (vasculitis, cutaneous vasculitis),
respiratory distress (including pneumonitis and pulmonary oedema), anaphylactic reactions, toxic
epidermal necrolysis.
Musculoskeletal/Connective Tissue: arthritis, stiffness lower extremity, muscle spasm,
weakness.
Nervous System: stress related disorder, tremor, disturbing dreams, restlessness.
Renal/Genitourinary: urination abnormality, renal dysfunction, interstitial nephritis.
Respiratory: epistaxis.
Special Senses: eye disturbance -other, eyelid abnormality, visual field abnormality, medication
bad taste, transient blurred vision.
Postmarketing Experience: As with other angiotensin-II receptor antagonists, rare cases of
hypersensitivity reactions (urticaria, angioedema) have been reported. The following have also
been reported during post-marketing surveillance: vertigo, asthenia, hyperkalemia, myalgia,
jaundice, elevated liver function tests, hepatitis, arthralgia, tinnitus and impaired renal function
including cases of renal failure in patients at risk.
Rare cases of rhabdomyolysis have been reported in patients receiving angiotensin II receptor
blockers.
DOSAGE AND ADMINISTRATION
Avapro HCT should not be initiated as first-line therapy. The daily dose can be administered with
or without food.
Replacement Therapy
The combination may be substituted for the titrated components at the same dose level.
Dose Titration by Clinical Effect
When clinically appropriate, direct change from monotherapy to the fixed combinations may be
considered:



Avapro HCT 150/12.5mg may be administered to patients whose blood pressure is not
adequately controlled with hydrochlorothiazide or irbesartan 150 mg alone.
Avapro HCT 300/12.5 mg may be administered to patients insufficiently controlled by
irbesartan 300 mg or by Avapro HCT 150/12.5 mg.
Avapro HCT 300/25 mg may be administered to patients insufficiently controlled by Avapro
HCT 300/12.5 mg.
Doses higher than 300 mg irbesartan/25 mg hydrochlorothiazide once daily are not
recommended. When necessary, Avapro HCT may be administered with another antihypertensive
drug.
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Patients with Intravascular Volume Depletion
In severely volume-depleted and/or sodium-depleted patients, such as those treated vigorously
with diuretics, the condition should be corrected prior to administration of Avapro HCT.
Elderly Patients
No dosage reduction is generally necessary for daily dosage of irbesartan 150mg/
hydrochlorothiazide 12.5mg in the elderly.
Patients with Renal Impairment
No dosage reduction is generally necessary for daily dosage of irbesartan 150mg/
hydrochlorothiazide 12.5mg in patients with mild-to-moderate renal impairment (creatinine
clearance >30mL/min).
Patients with Hepatic Impairment
No dosage reduction is thought to be necessary in patients with mild to moderate hepatic
impairment as the pharmacokinetics of neither irbesartan nor hydrochlorothiazide are affected by
hepatic impairment. Due to the hydrochlorothiazide component, Avapro HCT should be used
with caution in patients with severe hepatic impairment. (see PRECAUTIONS - Impaired
Hepatic Function).
OVERDOSAGE
Experience in adults exposed to irbesartan doses of up to 900 mg/day for 8 weeks revealed no
toxicity. No specific information is available on the treatment of overdosage with Avapro HCT.
The patient should be closely monitored, and the treatment should be symptomatic and
supportive, including fluid and electrolyte replacement. Irbesartan is not removed from the body
by haemodialysis.
The most common signs and symptoms observed in adults exposed to hydrochlorothiazide are
those caused by electrolyte depletion (hypokalemia, hypochloremia, hyponatremia) and
dehydration resulting from excessive diuresis. If a cardiac glycoside (e.g., digoxin) or other
antiarrhythmic drugs (e.g., sotalol) has also been administered, hypokalemia may accentuate
cardiac arrhythmias. The degree to which hydrochlorothiazide is removed by haemodialysis has
not been established.
For information on the management of overdose, contact the Poison Information Centre on
131126 (Australia).
PRESENTATION AND STORAGE CONDITIONS
Avapro HCT 150/12.5 tablets which contain 150mg of irbesartan and 12.5mg of
hydrochlorothiazide are peach to mottled peach coloured, biconvex, oval, film-coated tablets
debossed with a heart shape on one side and with “2875” on the other side. Pack size - Blisters :
3, 5, 7*, 14, 28, 30*, 56 & 98
Avapro HCT 300/12.5 tablets which contain 300mg of irbesartan and 12.5mg of
hydrochlorothiazide are peach to mottled peach coloured, biconvex, oval, film-coated tablets
debossed with a heart shape on one side and “2876” on the other side. Pack size - Blisters: 3, 5,
7*, 14, 28, 30*, 56 & 98
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Avapro HCT 300/25 tablets which contain 300mg of irbesartan and 25mg of hydrochlorothiazide
are pink, biconvex, oval, film-coated tablets debossed with a heart shape on one side and “2788”
on the other side. Pack size - Blisters: 3, 5,7*, 14, 28, 30*, 56 & 98 tablets.
* Indicates the packs marketed in Australia.
Storage
Store below 250C.
NAME AND ADDRESS OF SPONSOR
sanofi-aventis australia pty ltd
12-24 Talavera Road
Macquarie Park NSW 2113
Australia
POISON SCHEDULE OF THE MEDICINE
Schedule 4.
DATE OF FIRST INCLUSION IN THE ARTG (150/12.5 mg and 300/12.5 mg): 18 May
2005
DATE OF FIRST INCLUSION IN THE ARTG (300/25 mg): 18 April 2007
DATE OF MOST RECENT AMENDMENT: 26 June 2015
Avapro HCT is a sanofi-aventis trademark.
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